Differential requirements of protein geranylgeranylation for the virulence of human pathogenic fungi

Ana Camila Oliveira Souza, Qusai Al Abdallah, Kaci DeJarnette, Adela Martin-Vicente, Ashley V. Nywening, Christian DeJarnette, Emily A. Sansevere, Wenbo Ge, Glen Palmer, Jarrod Fortwendel

Research output: Contribution to journalArticle

Abstract

Protein prenylation is a crucial post-translational modification largely mediated by two heterodimeric enzyme complexes, farnesyltransferase and geranylgeranyltransferase type-I (GGTase-I), each composed of a shared α-subunit and a unique β-subunit. GGTase-I enzymes are validated drug targets that contribute to virulence in Cryptococcus neoformans and to the yeast-to-hyphal transition in Candida albicans. Therefore, we sought to investigate the importance of the α-subunit, RamB, and the β-subunit, Cdc43, of the A. fumigatus GGTase-I complex to hyphal growth and virulence. Deletion of cdc43 resulted in impaired hyphal morphogenesis and thermo-sensitivity, which was exacerbated during growth in rich media. The Δcdc43 mutant also displayed hypersensitivity to cell wall stress agents and to cell wall synthesis inhibitors, suggesting alterations of cell wall biosynthesis or stress signaling. In support of this, analyses of cell wall content revealed decreased amounts of β-glucan in the Δcdc43 strain. Despite strong in vitro phenotypes, the Δcdc43 mutant was fully virulent in two models of murine invasive aspergillosis, similar to the control strain. We further found that a strain expressing the α-subunit gene, ramB, from a tetracycline-inducible promoter was inviable under non-inducing in vitro growth conditions and was virtually avirulent in both mouse models. Lastly, virulence studies using C. albicans strains with tetracycline-repressible RAM2 or CDC43 expression revealed reduced pathogenicity associated with downregulation of either gene in a murine model of disseminated infection. Together, these findings indicate a differential requirement for protein geranylgeranylation for fungal virulence, and further inform the selection of specific prenyltransferases as promising antifungal drug targets for each pathogen.

Original languageEnglish (US)
Pages (from-to)511-526
Number of pages16
JournalVirulence
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2019

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Protein Prenylation
Virulence
Fungi
Cell Wall
Tetracycline
Candida albicans
Growth
Dimethylallyltranstransferase
Farnesyltranstransferase
Cryptococcus neoformans
Aspergillosis
Glucans
Enzymes
Post Translational Protein Processing
Morphogenesis
Pharmaceutical Preparations
Genes
Hypersensitivity
Down-Regulation
Yeasts

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

Cite this

Souza, A. C. O., Al Abdallah, Q., DeJarnette, K., Martin-Vicente, A., Nywening, A. V., DeJarnette, C., ... Fortwendel, J. (2019). Differential requirements of protein geranylgeranylation for the virulence of human pathogenic fungi. Virulence, 10(1), 511-526. https://doi.org/10.1080/21505594.2019.1620063

Differential requirements of protein geranylgeranylation for the virulence of human pathogenic fungi. / Souza, Ana Camila Oliveira; Al Abdallah, Qusai; DeJarnette, Kaci; Martin-Vicente, Adela; Nywening, Ashley V.; DeJarnette, Christian; Sansevere, Emily A.; Ge, Wenbo; Palmer, Glen; Fortwendel, Jarrod.

In: Virulence, Vol. 10, No. 1, 01.01.2019, p. 511-526.

Research output: Contribution to journalArticle

Souza, ACO, Al Abdallah, Q, DeJarnette, K, Martin-Vicente, A, Nywening, AV, DeJarnette, C, Sansevere, EA, Ge, W, Palmer, G & Fortwendel, J 2019, 'Differential requirements of protein geranylgeranylation for the virulence of human pathogenic fungi', Virulence, vol. 10, no. 1, pp. 511-526. https://doi.org/10.1080/21505594.2019.1620063
Souza ACO, Al Abdallah Q, DeJarnette K, Martin-Vicente A, Nywening AV, DeJarnette C et al. Differential requirements of protein geranylgeranylation for the virulence of human pathogenic fungi. Virulence. 2019 Jan 1;10(1):511-526. https://doi.org/10.1080/21505594.2019.1620063
Souza, Ana Camila Oliveira ; Al Abdallah, Qusai ; DeJarnette, Kaci ; Martin-Vicente, Adela ; Nywening, Ashley V. ; DeJarnette, Christian ; Sansevere, Emily A. ; Ge, Wenbo ; Palmer, Glen ; Fortwendel, Jarrod. / Differential requirements of protein geranylgeranylation for the virulence of human pathogenic fungi. In: Virulence. 2019 ; Vol. 10, No. 1. pp. 511-526.
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